Obesity is a major public health problem in the United States. Obesity is characterized by an increase in fat mass. Two different adipose tissues are found in mammals. White adipose tissue (WAT) is the major site for energy storage; and brown adipose tissue (BAT) plays an important role in thermogenesis and energy expenditure. Increases in the amount and/or activities of classical brown adipocytes and brown-like (beige) adipocytes inhibit the development of obesity and other metabolic diseases. Resveratrol (RES), natural compounds found in red grapes, has a potential to increase classical brown adipocyte differentiation and might induce beige adipocytes formation. But its low aqueous solubility and poor target specificity along with a high level of hepatic metabolism limit its application in obesity. The purpose of this project is to synthesize RES encapsulated nanostructured lipid carriers (RES-NLCs) to increase the aqueous solubility, bioactivities and target specificity of RES to adipose stromal stem cells (ASC), with the goal of preventing and reversing obesity. The stromal fractions of WAT and BAT contain ASC, which can be differentiated into brown adipocytes and white adipocytes, respectively. Recent studies demonstrate that ASC in WAT can also be differentiated into beige adipocytes. Inducing brown and beige adipocytes formation is a promising strategy in combating obesity. An ASC-targeting peptide has been reported to have more than 1000 times the binding affinity to ASC than stromal stem cells in other organs and tissues. Targeted delivery of RES via NLCs to ASC may prevent and reverse obesity through increasing brown and beige adipocytes formation. We have successfully synthesized RES-NLCs in our laboratory. In this project, we will incorporate ASC targeting peptides on the surface of RES-NLCs, which allows targeted delivery of RES to ASC. We will measure its target specificity in vivo using C57/BL6J mice and an IVIS(r) Lumina XR in-vivo imaging system. The anti-obesity activities will be evaluated in a mouse model of diet-induced obesity and underlying mechanisms of adipose-targeting RES-NLCs will be characterized using adipose-derived stromal cells isolated from the treated or the control mice ex vivo. As compared to native RES, adipose- targeting RES-NLCs may have a dose advantage in reducing triglyceride accumulation and inflammatory responses in white adipocytes, increasing brown adipocyte differentiation, and stimulating fatty acid oxidation in brown adipocytes. After intravenous administration to C57/BL6J mice, the pharmacokinetics and biodistribution of adipose-targeting RES-NLCs will be determined by measuring RES concentrations in blood and tissues collected from those mice. To determine the effects of adipose-targeting RES-NLCs on obesity in vivo, C57/BL6J mice will be fed with a high fat diet for 12 to 16 weeks. One experimental group will receive adipose-targeting RES-NLCs from week 1 until sacrifice (week 12), so that effects on the prevention of obesity can be evaluated. A second experimental group will receive adipose-targeting RES-NLCs from week 8 through week 16 so that effects on obesity treatment can be determined. Complete necropsies, blood tests including chemistry panel and CBC, and routine histological examinations on key tissues from mice will be performed to evaluate the safety of the adipose-targeting RES-NLCs. This innovation portends a potential breakthrough in the prevention and treatment of obesity. The proposed research will provide a novel strategy for the prevention and treatment of obesity by using natural compounds with minimized immunogenicity and side-effects but enhanced bioavailability and target specificity. The outcome of this project is expected to improve the quality of life and produce dramatic savings in the cost of medical care while providing undergraduate and graduate research experience.